The pathogenesis of hepatocellular carcinoma (HCC) related to habitual betel quid (BQ) chewing is unclear.Risk of HCCis increased with adverse hepatic fibrosis. This study aimed to assess the impact of chronic viralhepatitis on adverse hepatic fibrosis in HCC related to BQ chewing. This hospital-based case-control study enrolled200 pairs of age- and gender-matched patients with HCC and unrelated healthy controls. Serologic hepatitisB surface antigen (HBsAg), antibodies to hepatitis C virus (anti-HCV), α-fetoprotein (AFP), and surrogatemarkers for significant hepatic fibrosis were measured. Information on substance-use habits was obtained witha questionnaire. By analysis of surrogate markers for hepatic fibrosis, the prevalence of significant hepaticfibrosis in patients chewing BQ was between 45.8% and 91.7%, whereas that for patients without BQ chewingwas between 18.4% and 57.9%. The difference was significant (P <0.05 for each surrogate marker). Multivariateanalysis indicated that cirrhosis with Child-Pugh C (odds ratio (OR) = 3.28; 95% confidence interval (CI), 1.29-8.37), thrombocytopenia (OR = 3.92, 95% CI, 1.77-8.68), AFP >400 mg/L (OR = 2.21, 95% CI, 1.05-4.66) andmale gender (OR = 4.06, 95% CI, 1.29-12.77) were independent factors associated with habitual BQ chewing.In conclusion, adverse hepatic fibrosis and severe liver damage play important roles in the pathogenesis of BQrelatedHCC, which could be aggravated by chronic hepatitis B and hepatitis C. BQ-cessation programs andprevention of chronic HBV/HCV infection are needed to prevent HCC related to BQ chewing.